Process for the preparation of side chain-fluorinated alkyloxazoles, and new side chain-fluorinated alkyloxazoles

ABSTRACT

A process for the preparation of side chain-fluorinated alkyloxazoles, wherein hydroxyalkyloxazoles are reacted with an α,α-difluoroalkylamine at pressures of under 2 bar, in the presence of an inert solvent boiling at above 100° C. (at normal pressure), and new fluorinated alkyloxazoles.

The present invention relates to a particularly advantageous process for the preparation of fluorinated alkyloxazoles, which are important as intermediates for the preparation of antibiotics against gram-positive, gram-negative and against thiamphenicol-resistant microorganisms (see e.g. U.S. Pat. No. 4,235,892), and new side chain-fluorinated alkyloxazoles, which can be used for the same purpose.

U.S. Pat. No. 4,876,352 discloses that certain hydroxyalkyloxazolines can be reacted with α,α-difluoroalkylamines under pressure to give the corresponding fluoro derivatives. Suitable pressures here are e.g. those from 60 to 100 psi (about 4.2 to 7 bar); the solvent used is in particular methylene chloride (see claims 2 and 5 and the examples there). A disadvantage is working under pressure, which requires particular technical outlay, and the preferred use of methylene chloride, which for ecological reasons requires particular industrial safety measures.

There has now been found a process for the preparation of side chain-fluorinated alkyloxazoles of the formula (I) ##STR1## in which X¹ represents hydrogen, nitro, C₁ -C₆ -alkylthio, C₁ -C₆ -alkylsulpho, C₁ -C₆ -alkylthio substituted by fluorine, C₁ -C₆ -alkylsulphonyl substituted by fluorine or C₁ -C₆ -alkoxy substituted by fluorine,

X² represents C₁ -C₆ -alkyl, C₁ -C₆ -halogenoalkyl, C₅ -C₆ -cycloalkyl, C₂ -C₆ -alkenyl, C₂ -C₆ -alkinyl, C₁ -C₆ -alkoxy, C₇ -C₁₄ -aralkyl, C₈ -C₁₅ -aralkenyl, C₆ -C₁₂ -aryl or a heterocyclic radical having 4 to 11 C atoms and 1 to 3 oxygen, sulphur and/or nitrogen atoms,

X³ represents hydrogen or one of the radicals indicated in the case of X² or

X² and X³ together represent an oxygen atom and

X⁴ represents hydrogen or

X³ and X⁴ together represent a covalent bond,

in which the appropriate hydroxyalkyloxazole of the formula (II) ##STR2## in which the radicals X¹ to X⁴ have the meaning indicated in formula (I), is reacted with an α,α-difluoroalkylamine of the formula (III) ##STR3## in which Y¹ represents fluorine or chlorine,

Y² represents fluorine, chlorine or trifluoromethyl and

Y³ and Y⁴ independently of one another represent C₁ -C₆ -alkyl or

Y³ and Y⁴ together represent a saturated or unsaturated hydrocarbon chain having 4 to 5 C atoms,

which is characterized in that the reaction is carried out at pressures of under 2 bar and in the presence of an inert solvent boiling at above 100° C. (at normal pressure).

The compounds of the formula (II) where X¹ =hydrogen, nitro, C₁ -C₆ -alkylthio or C₁ -C₆ -alkylsulpho can be obtained, for example, according to EP-A1 130 633 or J. Chem. Soc. 1949, 589-594 or analogously thereto and the compounds of the formula (III), for example, according to U.S. Pat. No. 3,153,644 or Bull. Chem. Soc. Japan 1979, 3377 to 3380 or analogously thereto. The other compounds of the formula (II) can be prepared analogously to U.S. Pat. No. 2,816,915 and EP-A1 130 633 or J. Chem. Soc. 1949, 589-594.

In the formulae (I) and (II),

X¹ preferably represents C₁ -C₃ -alkylsulphonyl, in particular methylsulphonyl,

X² preferably represents phenyl or naphthyl, in particular phenyl and

X³ and X⁴ preferably together represent a covalent bond.

Preferred compounds of the formula (III) are:

N-(2-chloro-1,1,2-trifluoroethyl)diethylamine,

N-(1,1,2,3,3,3-hexafluoropropyl)diethylamine and

N-(1,1,2,3,3,3-hexafluoropropyl)dibutylamine.

Relative to 1 mol of a compound of the formula (II), 0.8 to 5 equivalents, for example, of a compound of the formula (III) can be employed. This amount is preferably 1.3 to 3 equivalents.

The process according to the invention is carried out at pressures of below 2 bar. Preferred pressures are those in the range of 0.1 to 1.5 bar. The process is particularly preferably carried out under normal pressure.

Suitable inert solvents boiling at above 100° C. at normal pressure are, for example, tetramethylene sulphone, chlorobenzene, dichlorobenzenes and trichlorobenzenes.

Suitable reaction temperatures are e.g. those in the range 70° to 150° C. Preferred temperatures are those in the range 90° to 120° C.

If desired, the reaction according to the invention can be carried out under an inert gas atmosphere, e.g. nitrogen.

The reaction mixture present after the reaction according to the invention can be worked up, for example, by diluting it with water, separating it into an organic and an aqueous phase, extracting the aqueous phase with a water-immiscible organic solvent, for example a water-immiscible ether, washing the organic phase with water, combining the organic phase and the organic extract from the aqueous phase and, optionally after drying, removing the solvent, e.g. by distillation in vacuo.

The process according to the invention has the advantage that it avoids working under pressure which is absolutely necessary according to U.S. Pat. No. 4,876,352 and in spite of this yields the compounds of the formula (I) in good yields.

The present invention furthermore relates to new side chain-fluorinated alkyloxazoles of the formula (I), in which X¹ represents fluorine-substituted C₁ -C₆ -alkylthio, fluorine-substituted C₁ -C₆ -alkylsulphonyl or fluorine-substituted C₁ -C₆ -alkoxy and the other symbols have the meaning indicated above. The C₁ -C₆ -alkylthio, C₁ -C₆ -alkylsulphonyl and C₁ -C₆ -alkoxy groups can in each case be monofluorinated or polyfluorinated or perfluorinated.

Preferred new fluorinated alkyloxazoles of the formula (I) are those in which X¹ represents methyl- or ethylthio substituted by 1 to 3 F atoms, methyl- or ethylsulphonyl substituted by 1 to 3 F atoms or methoxy or ethoxy substituted by 1 to 3 F atoms and the other symbols have the meaning indicated as preferred above.

EXAMPLES Example 1

20 g of D-threo-(-)-2-phenyl-4-(4-(methylsulphonyl)phenyl)-2-oxazole-5-methanol and 17.5 g of N-(1,1,2,3,3,3-hexafluoropropyl)diethylamine in 150 ml of chlorobenzene were heated to 100° C. and stirred at this temperature for 3.5 hours. The reaction mixture was diluted with water, the organic phase was separated off, the aqueous phase was extracted with methyl tert-butyl ether, the organic phase was washed with water, and the organic phase and the extract from the aqueous phase were combined. After drying it over sodium sulphate, the solvent was removed in vacuo. A yield of 85% of theory of D-threo-(-)-2-phenyl-4-(fluoromethyl)-5-(4-methylsulphonyl)-phenyl-2-oxazoline was obtained (determined by HPLC).

Example 2

10 g of D-threo-(-)-2-phenyl-4-(4-(methylsulphonyl)phenyl)-2-oxazole-5-methanol and 15 g of N-(1,1,2,3,3,3-hexafluoropropyl)diethylamine in 150 ml of tetramethylene sulphone were heated at 100° C. for 3 hours. The reaction mixture was worked up as described in Example 1.10 g of the same compound as in Example 1 were obtained, which corresponds to a yield of 82% of theory.

Example 3

10 g of D-threo-(-)-2-phenyl-4-(4-(methylsulphonyl)phenyl)-2-oxazole-5-methanol and 15 g of N-(1,1,2,3,3,3-hexafluoropropyl)diethylamine in 120 ml of a dichlorobenzene isomer mixture were heated to 110° C. and stirred at this temperature for 4 hours. Working up of the reaction mixture was carried out as described in Example 1. The same compound as in Example 1 was obtained in a yield of 79% of theory. 

What is claimed is:
 1. A process for the preparation of a side chain-fluorinated alkyloxazole of the formula ##STR4## in which X¹ represents hydrogen, nitro, C₁ -C₆ -alkylthio, C₁ -C₆ -alkylsulpho, C₁ -C₆ -alkylthio substituted by fluorine, C₁ -C₆ -alkylsulphonyl substituted by fluorine C₁ -C₆ -alkoxy substituted by fluorine,X² represents C₁ -C₆ -alkyl, C₁ -C₆ -halogenoalkyl, C₅ -C₇ -cycloalkyl, C₂ -C₆ -alkenyl, C₂ -C₆ -alkinyl, C₁ -C₆ -alkoxy, C₇ -C₁₄ -aralkyl, C₈ -C₁₅ -aralkenyl, C₆ -C₁₂ -aryl or a heterocyclic radical having 4 to 11 C atoms and 1 to 3 oxygen, sulphur and/or nitrogen atoms, X³ represents hydrogen or one of the radicals indicated in the case of X² or X² and X³ together represent an oxygen atom and X⁴ represents hydrogen or X³ and X⁴ together represent a covalent bond,in which the appropriate hydroxyalkyloxazole of the formula (II) ##STR5## in which the radicals X¹ to X⁴ have the meaning indicated in formula (I), is reacted with an α,α-difluoroalkylamine of the formula (III) ##STR6## in which Y¹ represents fluorine or chlorine, Y² represents fluorine, chlorine or trifluoromethyl and Y³ and Y⁴ independently of one another represent C₁ -C₆ -alkyl or Y³ and Y⁴ together represent a saturated or unsaturated hydrocarbon chain having 4 to 5 C atoms,in which process the reaction is carried out at pressures of 0.1 bar to atmospheric pressure and in the presence of an inert solvent boiling at above 100° C. (at normal pressure).
 2. The prorocess of claim 1, in which in the formulae (I) and (II),X¹ represents C₁ -C₃ -alkylsulphonyl, X² represents phenyl or naphthyl and X³ and X⁴ together represent a covalent bond.
 3. The process of claim 1, in which relative to 1 mol of a compound of the formula (II), 0.8 to 5 equivalents of a compound of the formula (III) are employed.
 4. The process of claim 1, in which the solvent employed is tetramethylene sulphone, chlorobenzene, a dichlorobenzene or a trichlorobenzene.
 5. The process of claim 1, which is carried out at 70° to 150° C.
 6. Side chain-fluorinated alkyloxazoles of the formula ##STR7## in which X¹ represents C₁ -C₆ -alkylthio substituted by fluorine, C₁ -C₆ -alkylsulphonyl substituted by fluorine or C₁ -C₆ -alkoxy substituted by fluorine,X² represents C₁ -C₆ -alkyl, C₁ -C₆ -halogenoalkyl, C₅ -C₇ -cycloalkyl, C₂ -C₆ -alkenyl, C₂ -C₆ -alkinyl, C₁ -C₆ -alkoxy, C₇ -C₁₄ -aralkyl, C₈ -C₁₅ -aralkenyl, C₆ -C₁₂ -aryl or a heterocyclic radical having 4 to 11 C. atoms and 1 to 3 oxygen, sulphur and/or nitrogen atoms, X³ represents hydrogen or one of the radicals indicated in the case of X² or X² and X³ together represent an oxygen atom and X⁴ represents hydrogen or X³ and X⁴ together represent a covalent bond.
 7. Fluorinated alkyloxazoles of claim 6, in which in formula (I') the radical X¹ is monofluorinated or polyfluorinated or perfluorinated.
 8. Fluorinated alkyloxazoles of claim 6, in which in formula (I'),X¹ represents methyl or ethylthio, methyl or ethylsulphonyl or methoxy or ethoxy which are substituted by 1 to 3 F atoms in each case, X² represents phenyl or naphthyl and X³ and X⁴ together represent a covalent bond. 